Adjuvant chemotherapy significantly improves disease-free and overall survival in early stage breast cancer. “Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials” Lancet 2005; 365(9472):1687-717. Anthracycline-containing regimens (e.g., doxorubicin and others), as compared with non-anthracycline-containing regimens, have been shown to further reduce recurrence and mortality rates. Over the past decades, taxanes, such as paclitaxel and docetaxel, have also emerged as effective chemotherapy agents for breast cancer and other malignancies. The addition of taxanes into the adjuvant breast cancer setting resulted in a significant improvement for disease-free survival and/or overall survival. De Laurentiis M. Cancello G, D'Agostino D, et al. “Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials” J Clin Oncol 2008: 26(1):44-53. The B-28 randomized clinical trial from the National Surgical Adjuvant Breast and Bowel Project (NSABP), for example, compared the treatment outcome achieved by sequential addition of paclitaxel to a doxorubicin plus cyclophosphamide regimen, compared with doxorubicin plus cyclophosphamide alone, in patients with axillary node positive breast cancer. The addition of paclitaxel alter doxorubicin plus cyclophosphamide was found to significantly improve disease-free survival but not overall survival. Mamounas E P, Bryant J, Lembersky B, et al. “Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP 8-28” J Clin Oncol 2005; 23(16):3686-96.
However, not all patients benefit from treatment with taxanes. Moreover, treatment with these drugs is expensive, and causes substantial morbidity and occasional life-threatening toxic effects, including neuropathy, neutropenia, leucopenia, anemia, hair loss, muscle/joint pain, nausea, vomiting and diarrhea. Other less frequent serious side effects include abnormal sensations (burning or tingling), thrombocytopenia and blood clotting problems, sores in the mouth or intestinal tract, change in electrocardiogram, and hypotension. Given these facts, the identification of biomarkers that reliably predict which patients are likely to benefit from treatment with a taxane is of critical importance.
Currently, no biomarkers predictive of outcome in patients who received taxane-based chemotherapy have been identified. Recent meta-analyses found a significant disease-free benefit for women with breast cancer who received taxane-based therapy regardless of hormonal receptor status and HER2 status (DeLaurentis, et al, supra; Pritchard K I, Messersmith H, Elavathil L, Trudeau M, O'Malley F, Dhesy-Third B “HER-2 and topoisomerase II as predictors of response to chemotherapy” J Clin Oncol 2008; 26(5):736-44), but no biomarkers have been identified that are predictive of treatment outcome with taxanes.
Akt is a serine/threonine protein kinase (also known as protein kinase B) that has been implicated in the pathogenesis of cancer, and essential cellular processes including metabolism, cell growth, proliferation, cell cycle progression, survival and differentiation. Bhaskar P T, Hay N “The two TORCs and Akt” Dev Cell 2007; 12(4):487-502. Recent preclinical studies reported that Akt-Ser473 is phosphorylated by SIN-1-rictor-mTOR complex, which is required fir the cellular function such as survival (Jacinto E, Facchinetti V, Liu D, et al. “SIN1/MIP1 maintains rictor-mTOR complex integrity, and regulates Akt phosphorylation and substrate specificity” Cell 2006; 127(1):125-37) and actin cytoskeletal reorganization. Importantly, paclitaxel inhibits Akt phosphorylation at serine 473 and reduces the survival cancer cells. MacKeigan J P, Taxman D J, Hunter D, Earp H S, 3rd, Graves L M, Ting J P “Inactivation of the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway by the combined treatment of taxol and mitogen-activated protein kinase kinase inhibition” Clin Cancer Res 2002; 8(7):2091-9; Asakuma J, Sumitomo M, Asano T, Asano T, Hayakawa M “Selective Akt inactivation and tumor necrosis actor-related apoptosis-inducing ligand sensitization of renal cancer cells by low concentrations of paclitaxel” Cancer Res 2003: 63(6):1365-70. Phosphorylation of Akt at serine 473 (pAkt) in breast cancer patients has been associated with tumor relapse with distant metastasis (Perez-Tenorio G, Stal O “Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients” Br J Cancer 2002; 86(4):540-5), and poor outcome to hormonal therapy (Kirkegaard T, Witton C J McGlynn L M, et al. “AKT activation predicts outcome in breast cancer patients treated with tamoxifen” J Pathol 2005; 207(2):139-46). However, prior to the studies reported herein, a link between the pAkt status of cancers to the efficacy of taxane treatment has not been evaluated.